Cellular and molecular mechanisms underlying DDX3X syndrome

Abstract Mutations in DDX3X are strongly associated with autism spectrum disorder (ASD), and may account for 1-3% of unexplained developmental delay (DD) in females, making this one of the most common of neurodevelopmental disorders. DDX3X is considered a high confidence ASD gene by SFARI gene. DDX3X encodes an RNA-binding protein of the DEAD-box helicase family.

While broadly implicated in mRNA metabolism, DDX3X is best characterized as a translational regulator. Despite the robust link between DDX3X and ASD, virtually nothing is known about DDX3X function in the developing brain nor the mechanisms by which DDX3X mutations perturb cellular function. Further, it remains largely unknown how DDX3X impacts neural progenitors and

how it controls translation of its targets. This limits our understanding of the causes of ASD for this common condition and the potential for therapeutic intervention. Our proposal addresses these gaps by investigating how DDX3X mutations impair brain development and protein synthesis. Our preliminary data indicates requirements for DDX3X in neural progenitors and

suggests that translational regulation may be relevant for disease. This has led to our central hypothesis that DDX3X mutations impair neurogenesis by disrupting the progenitor cell cycle and translation of key targets. To address this hypothesis we will: Define how DDX3X loss of function impairs cell fate specification in mouse models, determine how DDX3X missense mutations

impair human neural progenitor function and differentiation, and identify the mechanism(s) by which genetic variants in DDX3X alter protein synthesis. Our diverse scientific approaches enable this multifaceted understanding of DDX3X function and developmental role. Upon completion of this study we will gain fundamental insights into DDX3X biology and guide a framework for

therapeutic intervention.